19-nor vitamin D compounds

ABSTRACT

This invention provides a novel class of vitamin D-related compounds, namely the 1 alpha -hydroxy-19-nor-vitamin D analogs, as well as a general method for their chemical synthesis. The compounds exhibit pronounced activity in arresting the proliferation of undifferentiated cells, including malignant cells, and in inducing their differentiation, and thus represent novel therapeutic agents for the treatment of malignant and other diseases characterized by the proliferative growth of undifferentiated cells. Formulations for therapeutic use and treatment methods are also provided.

This invention was made with United States government support awarded bythe Department of Health and Human Services (NIH), Grant number:DK-14881. The United States Government has certain rights in thisinvention.

This application is a continuation of application Ser. No. 08/281,261filed Jul. 27, 1994, which is a divisional of application Ser. No.08/123,485 filed Sep. 17, 1993 now U.S. Pat. No. 5,342,975, which inturn is a divisional of Ser. No. 07/960,241 filed Oct. 13, 1992, nowU.S. Pat. No. 5,246,925, which in turn is a continuation of Ser. No.07/879,706 filed May 5, 1992, now abandoned, which in turn is acontinuation of Ser. No. 07/557,400 filed Jul. 23, 1990, now abandoned,which in turn is a divisional of Ser. No. 07/481,354 filed Feb. 16,1990, now U.S. Pat. No. 5,237,110, which in turn is acontinuation-in-part application of Ser. No. 07/321,030 filed Mar. 9,1989, now abandoned.

This invention relates to biologically active vitamin D compounds. Morespecifically, the invention relates to 19-nor-analogs of 1α-hydroxylatedvitamin D compounds and to a general process for their preparation.

BACKGROUND

The 1α-hydroxylated metabolites of vitamin D--most importantly1α,25-dihydroxyvitamin D₃ and 1α,25-dihydroxyvitamin D₂ --are known ashighly potent regulators of calcium homeostasis in animals and humans,and more recently their activity in cellular differentiation has alsobeen established. As a consequence, many structural analogs of thesemetabolites, such as compounds with different side chain structures,different hydroxylation patterns, or different stereochemistry, havebeen prepared and tested. Important examples of such analogs are1α-hydroxyvitamin D₃, 1α-hydroxyvitamin D₂, various side chainfluorinated derivatives of 1α,25-dihydroxyvitamin D₃, and side chainhomologated analogs. Several of these known compounds exhibit highlypotent activity in vito or in vitro, and possess advantageous activityprofiles and thus are in use, or have been proposed for use, in thetreatment of a variety of diseases such as renal osteodystrophy, vitaminD-resistant rickets, osteoporosis, psoriasis, and certain malignancies.

DISCLOSURE AND DESCRIPTION OF THE INVENTION

A class of 1α-hydroxylated vitamin D compounds not known heretofore arethe 19-nor-analogs, i.e. compounds in which the ring A exocyclicmethylene group (carbon 19) typical of all vitamin D system has beenremoved and replaced by two hydrogen atoms. Structurally these novelanalogs are characterized by the general formula I shown below: ##STR1##where X¹ and X² are each selected from the group consisting of hydrogenand acyl, and where the group R represents any of the typical sidechains known for vitamin D type compounds. Thus, R may be an alkyl,hydrogen, hydroxyalkyl or fluoroalkyl group, or R may represent thefollowing side chain: ##STR2## wherein R¹ represents hydrogen, hydroxyor O-acyl, R² and R³ are each selected from the group consisting ofalkyl, hydroxyalkyl and fluoroalkyl, or, when taken together representthe group--(CH₂)_(m) --where m is an integer having a value of from 2 to5, R⁴ is selected from the group consisting of hydrogen, hydroxy,fluorine, O-acyl, alkyl, hydroxyalkyl and fluoroalkyl, R⁵ is selectedfrom the group consisting of hydrogen, fluorine, alkyl, hydroxyalkyl andfluoroalkyl, or, R⁴ and R⁵ taken together represent double-bondedoxygen, R⁶ and R⁷ are each selected from the group consisting ofhydrogen, hydroxy, O-acyl, fluorine and alkyl, or, R⁶ and R⁷ takentogether form a carbon-carbon double bond, and wherein n is an integerhaving a value of from 1 to 5, and wherein the carbon at any one ofpositions 20, 22, or 23 in the side chain may be replaced by an O, S, orN atom.

Specific important examples of side chains are the structuresrepresented by formulas (a), (b), (c), (d) and (e) below, i.e. the sidechain as it occurs in 25-hydroxyvitamin D₃ (a); vitamin D₃ (b);25-hydroxyvitamin D₂ (c); vitamin D₂ (d); and the C-24-epimer of25-hydroxyvitamin D₂ (e). ##STR3## In this specification and the claims,the term `alkyl` signifies an alkyl radical of 1 to 5 carbons in allisomeric forms, such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, pentyl, etc., and the terms `hydroxyalkyl` and `fluoroalkyl`refer to such an alkyl radical substituted by one or more hydroxy orfluoro groups respectively, and the term `acyl` means an aliphatic acylgroup of 1 to 5 carbons, such as formyl, acetyl, propionyl, etc. or anaromatic acyl group such as benzoyl, nitrobenzoyl or halobenzoyl. Theterm `aryl` signifies a phenyl-, or an alkyl-, nitro- orhalo-substituted phenyl group.

The preparation of 1α-hydroxy-19-nor-vitamin D compounds having thebasic structure shown above can be accomplished by a common generalmethod, using known vitamin D compounds as starting materials. Suitablestarting materials are, for example, the vitamin D compounds of thegeneral structure II: ##STR4## where R is any of the side chains asdefined above. These vitamin D starting materials are known compounds,or compounds that can be prepared by known methods.

Using the procedure of DeLuca et al. (U.S. Pat. No. 4,195,027), thestarting material is converted to the corresponding1α-hydroxy-3,5-cyclovitamin D derivative, having the general structureIII below, where X represents hydrogen and Q represents an alkyl,preferably methyl: ##STR5## So as to preclude undesired reaction of the1α-hydroxy group in subsequent steps, the hydroxy group is converted tothe corresponding acyl derivative, i.e. the compound III shown above,where X represents an acyl group, using standard acylation procedures,such as treatment with an acyl anhydride or acyl halide in pyridine atroom temperature or slightly elevated temperature (30°-70° C.) It shouldbe understood also that whereas the process of this invention isillustrated here with acyl protection of hydroxy functions, alternativestandard hydroxy-protecting groups can also be used, such as, forexample, alkylsilyl or alkoryalkyl groups. Such protecting groups arewell-known in the art (e.g. trimethylsilyl, triethylsilyl,t.-butyldimethylsilyl, or tetrahydrofuranyl, methoxymethyl), and theiruse is considered a routine modification of experimental detail withinthe scope of the process of this invention.

The derivative as obtained above is then reacted with osmium tetroxide,to produce the 10,19-dihydroxy analog, IV (where X is acyl), which issubjected to diol cleavage using sodium metaperiodate or similar vicinaldiol cleavage reagents (e.g. lead tetraacetate) to obtain the10-oxo-intermediate, having the structure V below (where X is acyl):##STR6## These two consecutive steps can be carried out according to theprocedures given by Paaren et el. J. Org. Chem. 48, 3819 (1983)!. If theside chain unit, R, carries vicinal diols (e.g. 24,25-dihydroxy- or25,26-dihydroxy, etc.), these, of course, also need to be protected,e.g. via acylation, silylation, or as the isopropylidene derivativeprior to the periodate cleavage reactions.

In most cases, the acylation of the 1α-hydroxy group as mentioned abovewill simultaneously effect the acylation of side chain hydroxyfunctions, and these acylation conditions can, of course, beappropriately adjusted (e.g. elevated temperatures, longer reactiontimes) so as to assure complete protection of side chain vicinal diolgroupings.

The next step of the process comprises the reduction of the 10-oxo-groupto the corresponding 10-alcohol having the structure VI shown below(where X is acyl and Y represents hydroxy). When X is acyl, thisreduction is carried out conveniently in an organic solvent at fromabout 0° C. to about room temperature, using NaBH₄ or equivalent hydridereducing agents, selective for the reduction of carbonyl groups withoutcleaving ester functions. Obviously, when X is a hydroxy-protectinggroup that is stable to reducing agents, any of the other hydridereducing agents (e.g. LiAlH₄, or analogous reagents) may be employedalso. ##STR7## The 10-hydroxy intermediate is then treated with analkyl- or arylsulfonylhalide (e.g. mathanesulfonylchloride) in asuitable solvent (e.g. pyridine) to obtain the corresponding 10-0-alkyl-or arylsulfonyl derivative (the compound having the structure shown VIabove, where Y is alkyl-SO₂ O-, or aryl-SO₂ O-, and this sulfonateintermediate is then directly reduced, with lithium aluminum hydride, orthe analogous known lithium aluminum alkyl hydride reagents in an ethersolvent, at a temperature ranging from 0° C. to the boiling temperatureof the solvent, thereby displacing the sulfonate group and obtaining the10-deoxy derivative, represented by the structure VI above, where X andY are both hydrogen. As shown by the above structure, a 1-0-acylfunction in the precursor compound V is also cleaved in this reductionstep to produce the free 1α-hydroxy function, and any 0-acyl protectinggroup in the side chain would, of course, likewise be reduced to thecorresponding free alcohol function, as is well understood in the art.If desired, the hydroxy groups at C-1 (or hydroxy groups in the sidechain) can be reprotected by acylation or silylation or ether formationto the corresponding acyl, alkylsilyl or alkoxyalkyl derivative, butsuch protection is not required. Alternative hydroxy-protecting groups,such as alkylsilyl or alkoxyalkyl groups would be retained in thisreduction step, but can be removed, as desired, at this or later stagesin the process by standard methods known in the art.

The above 1α-hydroxy-10-deoxy cyclovitamin D intermediate is nextsolvolyzed in the presence of a low-molecular weight organic acid, usingthe conditions of DeLuca et el. (U.S. Pat. Nos. 4,195,027 and4,260,549). When the solvolysis is carried out in acetic acid, forexample, there is obtained a mixture of 1α-hydroxy-19-nor-vitamin D3-acetate and 1α-hydroxy-19-nor-vitamin D 1-acetate (compounds VII andVIII, below), and the analogous 1- and 3-acylates are produced, whenalternative acids are used for solvolysis. ##STR8## Direct basichydrolysis of this mixture under standard conditions then produces thedesired 1α-hydroxy-19-nor-vitamin D compounds of structure I above(where X¹ and X² are hydrogen). Alternatively, the above mixture ofmonacetates may also be separated (e.g. by high pressure liquidchromatography) and the resulting 1-acetate and 3-acetate isomers may besubjected separately to hydrolysis to obtain the same final product fromeach, namely the 1α-hydroxy-19-nor-vitamin D compounds of structure I.Also the separated monoacetates of structure VII or VIII or the free1,3-dihydroxy compound can, of course, be reacylated according tostandard procedures with any desired acyl group, so as to produce theproduct of structure I above, where X¹ and X² represent acyl groupswhich may be the same or different.

Biological Activity of 1α-Hydroxy-19-Nor-Vitamin D Compounds

The novel compounds of this invention exhibit an unexpected pattern ofbiological activity, namely high potency in promoting thedifferentiation of malignant cells and little or no activity incalcifying bone tissue. This is illustrated by the biological assayresults obtained for 1α,25-dihydroxy-19-nor-vitamin D₃ (compounds Ia),which are summarized in Tables 1 and 2, respectively. Table 1 shows acomparison of the activity of the known active metabolite1α,25-dihydroxyvitamin D₃ and the 19-nor analog (Ia) in inducing thedifferentiation of human leukemia cells (HL-60 cells) in culture tonormal cells (monocytes). Differentiation activity was assessed by threestandard differentiation assays, abbreviated in Table 1 as NBT(nitroblue tetrazolium reduction), NSE (non-specific esterase activity),and PHAGO (phagocytosis activity). The assays were conducted accordingto known procedures, as given, for example, by DeLuca et al. (U.S. Pat.No. 4,717,721) and Ostrem et al., J. Biol. Chem. 262, 14164, 1987). Foreach assay, the differentiation activity of the test compounds isexpressed in terms of the percent of HL-60 cells having differentiatedto normal cells in response to a given concentration of test compound.

The results summarized in Table 1 clearly show that the new analog,1α,25-dihydroxy-19-nor-vitamin D₃ (Ia) is as potent as1α,25-dihydroxyvitamin D₃ in promoting the differentiation of leukemiacells. Thus in all three assays close to 90% of the cells are induced todifferentiate by 1α,25-dihdyroxy-vitamin D₃ at a concentration of 1×10⁻⁷molar, and the same degree of differentiation (i.e. 90, 84 and 90%) isachieved by the 19-nor analog (Ia).

                  TABLE 1                                                         ______________________________________                                        Differentiation of HL-60 Cells                                                             % Differentiated Cells                                                        (mean ± SEM)                                                               NBT     NSE     PHAGO                                            ______________________________________                                        1α,25-dihydroxyvitamin D.sub.3                                          (moles/liter)                                                                 1 × 10.sup.-7                                                                          86 ± 2 89 ± 1                                                                             87 ± 3                                    1 × 10.sup.-8                                                                          60 ± 2 60 ± 3                                                                             64 ± 2                                    1 × 10.sup.-9                                                                          33 ± 2 31 ± 2                                                                             34 ± 1                                    1α,25-Dihydroxy-19-nor-                                                 vitamin D.sub.3, (Ia)                                                         (moles/liter)                                                                 2 × 10.sup.-7                                                                          94 ± 2 95 ± 3                                                                             94 ± 2                                    1 × 10.sup.-7                                                                          90 ± 4 84 ± 4                                                                             90 ± 4                                    5 × 10.sup.-8                                                                          72 ± 3 73 ± 3                                                                             74 ± 3                                    1 × 10.sup.-8                                                                          61 ± 3 60 ± 3                                                                             56 ± 1                                    1 × 10.sup.-9                                                                          32 ± 1 31 ± 1                                                                             33 ± 1                                    ______________________________________                                    

In contrast to the preceding results, the new 19-nor analog (Ia)exhibits no activity in an assay measuring the calcification of bone, atypical response elicited by vitamin D compounds. Relevant data,representing the results of an assay comparing the bone calcificationactivity in rats of 1α,25-dihydroxyvitamin D₃ and1α,25-dihydroxy-19-nor-vitamin D₃ (Ia), are summarized in Table 2. Thisassay was conducted according to the procedure described by Tanaka etal., Endocrinology 92, 417 (1973).

The results presented in Table 2 show the expected bone calcificationactivity of 1α,25-dihydroxyvitamin D₃ as reflected by the increase inpercent bone ash, and in total ash at all dose levels. In contrast, the19-nor analog Ia exhibits no activity at all three dose levels, whencompared to the vitamin D-deficient (-D) control group.

                  TABLE 2                                                         ______________________________________                                        Calcification Activity                                                                  Amount                                                                        Administered*                                                                              % Ash      Total Ash (mg)                              Compound  (pmoles/day/7 days)                                                                        (mean ± SEM)                                                                          (mean ± SEM)                             ______________________________________                                        D (control)                                                                             0            19 ± 0.8                                                                              23 ± 1.2                                 1α,25-dihydroxy-                                                                  32.5         23 ± 0.5                                                                              34 ± 1.6                                 vitamin D.sub.3                                                                         65.0         26 ± 0.7                                                                              36 ± 1.1                                           325.0        28 ± 0.9                                                                              40 ± 1.9                                 1α,25-                                                                            32.5         22 ± 0.9                                                                              28 ± 1.6                                 dihydroxy-19-                                                                           65.0         19 ± 1.5                                                                              28 ± 3.4                                 vitamin D.sub.3 (Ia)                                                                    325.0        19 ± 1.2                                                                              30 ± 2.4                                 ______________________________________                                         *Each assay grop comprised 6 rats, receiving the indicated amount of test     compound by intraperitoneal injection daily for a period of seven days.  

Thus the new 19-nor analog shows a selective activity profile combininghigh potency in inducing the differentiation of malignant cells withvery low or no bone calcification activity. The compounds of this novelstructural class, therefore, can be useful as therapeutic agents for thetreatment of malignancies. Because the differentiative activity ofvitamin D compounds on keratinocytes of skin (Smith et al., J. Invest.Dermatol. 86, 709, 1986; Smith et al., J. Am. Acad. Dermatol. 19, 516,1988) is believed to be an indication of successful treatment ofpsoriasis (Takamoto et al., Calc. Tissue Int. 39, 360, 1986), thesecompounds should prove useful in treating this and other skin disorderscharacterized by proliferation of undifferentiated skin cells. Thesecompounds should also find use in the suppression of parathyroid tissue,as for example, in cases of secondary hyperparathyroidism found in renaldisease (Slatopolsky et al., J. Clin. Invest. 74, 2136, 1984).

For treatment purposes, the novel compounds of this invention can beformulated as solutions in innocuous solvents, or as emulsions,suspensions or dispersions in suitable innocuous solvents or carriers,or as pills, tablets or capsules, containing solid carriers according toconventional methods known in the art. For topical applications thecompounds are advantageously formulated as creams or ointments orsimilar vehicle suitable for topical applications. Any such formulationsmay also contain other pharmaceutically-acceptable and non-toxicexcipients such as stabilizers, anti-oxidants, binders, coloring agentsor emulsifying or taste-modifying agents.

The compounds are advantageously administered by injection, or byintravenous infusion of suitable sterile solutions, or in the form oforal doses via the alimentary canal, or topically in the form ofointments, lotions, or in suitable transdermal patches. For thetreatment of malignant diseases, the 19-nor-vitamin D compounds of thisinvention are administered to subjects in dosages sufficient to inhibitthe proliferation of malignant cells and induce their differentiationinto normal monocyte-macrophages. Similarly, for the treatment ofpsoriasis, the compounds may be administered orally or topically inamounts sufficient to arrest the proliferation of undifferentiatedkeratinocytes, and in the treatment of hyperparathyroidism, thecompounds are administered in dosages sufficient to suppress parathyroidactivity, so as to achieve parathyroid hormone levels in the normalrange. Suitable dosage amounts are from 1 to 500 μg of compound per day,such dosages being adjusted, depending on diseases to be treated, itsseverity and the response or condition of the subject as well-understoodin the art.

This invention is more specifically described by the followingillustrative examples. In these examples specific products identified byRoman numerals and letters, i.e. Ia, Ib, . . . , IIa, IIb, . . . , etc.refer to the specific structures and side chain combinations identifiedin the preceding description.

EXAMPLE 1

Preparation of 1α,25-dihydroxy-19-nor-vitamin D₃ (Ia)

(a) 1α,25-Dihydroxy-3,5-cyclovitamin D₃ 1-acetate, 6-methyl ether: Using25-hydroxyvitamin D₃ (IIa) as starting material, the known1α,25-dihydroxy-3,5-cyclovitamin D₃ derivative IIIa (X=H) was preparedaccording to published procedures (DeLuca et al., U.S. Pat. No.4,195,027 and Paaren et al., J. Org. Chem. 45, 3252 (1980)). Thisproduct was then acetylated under standard conditions to obtain thecorresponding 1-acetate derivative IIIa (X=Ac).

(b) 10,19-Dihydro-1α,10,19,25-tetrahydroxy-3,5-cyclovitamin D₃1-acetate, 6-methyl ether (IVa): Intermediate IIIa (X=Ac) was treatedwith a slight molar excess of osmium tetroxide in pyridine according tothe general procedure described by Paaren et al. (J. Org. Chem. 48, 3819(1983)) to obtain the 10,19-dihydroxylated derivative IVa. Mass spectrumm/z (relative intensity), 506 (M⁺, 1), 488 (2), 474 (40), 425 (45), 396(15), 285 (5), 229 (30), 133 (45), 59 (80), 43 (100). ¹ H NMR (CDCl₃) δ0.52 (3H, s, 18-CH₃), 0.58 (1H, m, 3-H), 0.93 (3H, d, J=6.1 Hz, 21-CH₃),1.22 (6H, s, 26-CH₃ and 27-CH₃), 2.10 (3H, s, COCH₃), 3.25 (3H, s,6-OCH₃), 3.63 (2H, m, 19-CH₂), 4.60 (1H, d, J=9.2 Hz, 6-H), 4.63 (1H,dd, 1β-H), 4.78 (1H, d, J=9.2 Hz, 7-H).

(c) 1α,25-Dihydroxy-10-oxo-3,5-cyclo-19-nor-vitamin D₃ 1-acetate,6-methyl ether (Va): The 10,19-dihydroxylated intermediate IVa wastreated with a solution of sodium metaperiodate according to theprocedure given by Paaren et al. (J. Org. Chem. 48, 3819, 1983) toproduce the 10-oxo-cyclovitamin D derivative (Va, X=Ac). Mass spectrumm/z (relative intensity) 442 (M⁺ -MeOH) (18), 424 (8), 382 (15), 364(35), 253 (55), 225 (25), 197 (53), 155 (85), 137 (100). ¹ H NMR (CDCl₃)δ 0.58 (3H, s, 18-CH₃), 0.93 (3H, d, J=6.6 Hz, 21-CH₃), 1.22 (6H, s,26-CH₃ and 27-CH₃), 2.15 (s, 3-OCOCH₃), 3.30 (3H, s, 6-OCH₃), 4.61 (1H,d, J=9.1 Hz, 6-H), 4.71 (1H, d, J=9.6 Hz, 7-H), 5.18 (1H, m, 1β-H).

It has been found also that this diol cleavage reaction does not requireelevated temperatures, and it is, indeed, generally preferable toconduct the reaction at approximately room temperature.

(d) 1α-Acetoxy-10,25-dihydroxy-3,5-cyclo-19-nor-vitamin D₃ 6-methylether (VIa, X=Ac, Y=OH): The 10-oxo derivative Va (X=Ac) (2.2 mg, 4.6μmol) was dissolved in 0.5 ml of ethanol and to this solution 50 μl (5.3μmol) of a NaBH₄ solution (prepared from 20 mg of NaBH₄, 4.5 ml waterand 0.5 ml of 0.01 N NaOH solution) was added and the mixture stirred at0° C. for ca. 1.5 h, and then kept at 0° C. for 16 h. To the mixtureether was added and the organic phase washed with brine, dried overMgSO₄, filtered and evaporated. The crude product was purified by columnchromatography on a 15×1 cm silica gel column and the alcohol VIa (X=Ac,Y=OH) was eluted with ethyl acetate hexane mixtures to give 1.4 mg (3μmol) of product. Mass spectrum m/z (relative intensity) 476 (M⁺) (1),444 (85), 426 (18), 384 (30), 366 (48), 351 (21), 255 (35), 237 (48),199 (100), 139 (51), 59 (58).

(e) 1α,25-Dihydroxy-19-nor-vitamin D₃ (Ia, X¹ =X² =H): The 10-alcohol(VIa, X=Ac, Y=OH) (1.4 mg) was dissolved in 100 μl anhydrous CH₂ Cl₂ and10 μl (14 μmol) triethylamine solution prepared from 12 mg (16 μl )triethylamine in 100 μl anhydrous CH₂ Cl₂ !, followed by 7 μl (5.6 μmol)mesyl chloride solution (9 mg mesyl chloride, 6.1 μl, in 100 μlanhydrous CH₂ Cl₂) added at 0° C. The mixture was stirred at 0° C. for 2h. The solvents were removed with a stream of argon and the residue(comprising compound VIa, X=Ac, Y=CH₃ SO₂ O--) dissolved in 0.5 ml ofanhydrous tetrahydrofuran; 5 mg of LiAlH₄ was added at 0° C. and themixture kept at 0° C. for 16 h. Excess LiAlH₄ was decomposed with wetether, the ether phase was washed with water and dried over MgSO₄,filtered and evaporated to give the 19-nor product VIa (X=Y=H).

This product was dissolved in 0.5 ml of acetic acid and stirred at 55°C. for 20 min. The mixture was cooled, ice water added and extractedwith ether. The other phase was washed with cold 10% sodium bicarbonatesolution, brine, dried over MgSO₄, filtered and evaporated to give theexpected mixture of 3-acetoxy-1α-hydroxy- and 1α-acetoxy-3-hydroxyisomers, which were separated and purified by HPLC (Zorbax Sil column,6.4×25 cm, 2-propanol in hexane) to give about 70 μg each of compoundsVIIa and XIIIa. UV (in EtOH) λ_(max) 242.5 (OD 0.72), 251.5 (OD 0.86),260 (OD 0.57).

Both 19-nor-1,25-dihydroxyvitamin D₃ acetates VIIa and VIIIa werehydrolyzed in the same manner. Each of the monoacetates was dissolved in0.5 ml of ether and 0.5 ml 0.1N KOH in methanol was added. The mixturewas stirred under argon atmosphere for 2 h. More ether was added and theorganic phase washed with brine, dried over anhydrous MgSO₄, filteredand evaporated. The residue was dissolved in a 1:1 mixture of 2-propanoland hexane and passed through a Sep Pak column and washed with the samesolvent. The solvents were evaporated and the residue purified by HPLC(Zorbax Sil, 6.4×25 cm, 10% 2-propanol in hexane). The hydrolysisproducts of VIIa and VIIIa were identical and gave 66 μg of Ia (X¹ =X²=H). Mass spectrum (m/z relative intensity) 404 (M⁺) (100), 386 (41),371 (20), 275 (53), 245 (51), 180 (43), 135 (72), 133 (72), 95 (82), 59(18), exact mass calcd. for C₂₆ H₄₄ O₃ 404.3290, found 404.3272. ¹ H NMR(CDCl₃) δ 0.52 (3H, s, 18-CH₃), 0.92 (3H, d, J=6.9 Hz, 21-CH₃), 1.21(6H, s, 26-CH₃ and 27-CH₃), 4.02 (1H, m, 3α-H), 4.06 (1H, m, 1β-H), 5.83(1H, d, J=11.6 Hz, 7-H), 6.29 (1H, d, J=10.7 Hz, 6-H). UV (in EtOH),λ_(max) 243 (OD 0.725), 251.5 (OD 0.823), 281 (OD 0.598).

EXAMPLE 2

Preparation of 1α-hydroxy-19-nor-vitamin D₃ (Ib)

(a) With vitamin D₃ (IIb) as starting material, and utilizing theconditions of Example 1a, there is obtained known1α-hydroxy-3,5-cyclovitamin D₃ 1-acetate, 6-methyl ether, compound IIIb(X=Ac).

(b) By subjecting intermediate IIIb (X=Ac), as obtained in Example 2aabove to the conditions of Example 1b, there is obtained10,19-dihydro-1α,10,19-trihydroxy-3,5-cyclovitamin D₃ 1-acetate,6-methyl ether IVb (X=Ac).

(c) By treatment of intermediate IVb (X=Ac) with sodium metaperiodateaccording to Example 1c above, there is obtained1α-hydroxy-10-oxo-3,5-cyclo-19-nor-vitamin D₃ 1-acetate, 6-methyl etherVb (X=Ac).

(d) Upon reduction of the 10-oxo-intermediate Vb (X=Ac) under theconditions of Example 1d above, there is obtained1α-acetoxy-10-hydroxy-3,5-cyclo-19-nor-vitamin D₃ 6-methyl ether VIb(X=Ac, Y=OH).

(e) Upon processing intermediate VIb (X=Ac, Y=OH) through the proceduregiven in Example 1e above, there is obtained 1α-hydroxy-19-nor-vitaminD₃ (Ib, X¹ =X² =H).

EXAMPLE 3

Preparation of 1α,25-dihydroxy-19-nor-vitamin D₂

(a) Utilizing 25-hydroxyvitamin D₂ (IIc) as starting material andexperimental conditions analogous to those of Example 1a, there isobtained 1α,25-dihydroxy-3,5-cyclovitamin D₂ 1-acetate, 6-methyl ether,compound IIIc (X=Ac).

(b) Subjecting intermediate IIId (X=Ac), as obtained in Example 3aabove, to the reaction conditions of Example Ib, provides10,19-dihydro,1α,10,19,25-tetrahydroxy-3,5-cyclo-vitamin D₂ 1-acetate,6-methyl ether, IVc (X=Ac).

(c) By treatment of intermediate IVc (X=Ac) with sodium metaperiodateaccording to general procedures of Example 1c above, there is obtained1α,25-dihydroxy-10-oxo-3,5-cyclo-19-nor-vitamin D₂ 1-acetate, 6-methylether Vc (X=Ac).

(d) Upon reduction of the 10-oxo-intermediate Vc (X=Ac) under conditionsanalogous to those of Example 1d above, there is obtained1α-acetoxy-10,25-dihydroxy-3,5-cyclo-19-nor-vitamin D₂ 6-methyl etherVIc (X=Ac, Y=OH).

(e) Upon processing intermediate VIc (X=Ac, Y=OH) through the proceduralsteps given in Example 1e above, there is obtained1α,25-dihydroxy-19-nor-vitamin D₂ (Ic, X¹ =X² =H).

EXAMPLE 4

Preparation of 1α-hydroxy-19-nor-vitamin D₂

(a) With vitamin D₂ (IId) as starting material, and utilizing theconditions of Example 1a, there is obtained known1α-hydroxy-3,5-cyclovitamin D₂ 1-acetate, 6-methyl ether, compound IIId(X=Ac).

(b) By subjecting intermediate IIId (X=Ac), as obtained in Example 4aabove to the conditions of Example 1b, there is obtained10,19-dihydro-1α10,19-trihydroxy-3,5-cyclovitamin D₂ 1-acetate, 6-methylether, IVd (X=Ac).

(c) By treatment of intermediate IVb (X=Ac) with sodium metaperiodateaccording to Example 1c above, there is obtained1α-hydroxy-10-oxo-3,5-cyclo-19-nor-vitamin D₂ 1-acetate, 6-methyl ether,Vd (X=Ac).

(d) Upon reduction of the 10-oxo-intermediate Vd (X=Ac) under theconditions of Example 1d above, there is obtained1α-acetoxy-10-hydroxy-3,5-cyclo-19-nor-vitamin D₂ 6-methyl ether, VId(X=Ac, Y=OH).

(e) Upon processing intermediate VId (X=Ac, Y=OH) through the proceduregiven in Example 1e above, there is obtained 1α-hydroxy-19-nor-vitaminD₂ (Id, X¹ =X² =H).

We claim:
 1. A compound having the formula ##STR9## where R is a sidechain selected from the group consisting of alkyl, hydrogen,hydroxyalkyl, fluoroalkyl and a side chain of the formula ##STR10##wherein R¹ represents hydrogen, hydroxy or O-acyl, R² and R³ are eachselected from the group consisting of alkyl, hydroxyalkyl andfluoroalkyl, or, when taken together represent the group--(CH₂)_(m)--where m is an integer having a value of from 2 to 5, R⁴ is selectedfrom the group consisting of hydrogen, hydroxy, fluorine, O-acyl, alkyl,hydroxyalkyl and fluoroalkyl, R⁵ is selected from the group consistingof hydrogen, fluorine, alkyl, hydroxyalkyl and fluoroalkyl, or, R⁴ andR⁵ taken together represent double-bonded oxygen, R⁶ and R⁷ are eachselected from the group consisting of hydrogen, hydroxy, O-acyl,fluorine and alkyl, or, R⁶ and R⁷ taken together form a carbon-carbondouble bond, and wherein n is an integer having a value of from 1 to 5and wherein any of the groups --CH(CH₃)--, --CH(R⁷)--, or --CH(R⁶)-- atpositions 20, 22 and 23, respectively, may be replaced by an oxygenatom, Q represents an alkyl, X is selected from the group consisting ofhydrogen, acyl, alkylsilyl and alkoxyalkyl and Y is selected from thegroup consisting of hydroxy, hydrogen and protected hydroxy where theprotecting group is acyl, alkylsilyl or alkoxyalkyl.
 2. The compounds ofclaim 1 where R is a side chain of the formula ##STR11## Q is methyl andX is acyl.
 3. The compounds of claim 1 where R is a side chain of theformula ##STR12## Q is methyl and X is acyl.
 4. The compounds of claim 1where R is a side chain of the formula ##STR13## Q is methyl and X isacyl.
 5. The compounds of claim 1 where R is a side chain of the formula##STR14## Q is methyl and X is acyl.